Current Therapeutic Approaches to Renal Cell Carcinoma

VEGF Monoclonal Antibodies

Bevacizumab is a recombinant humanized monoclonal antibody that binds and neutralizes VEGF-A. Given overexpression of VEGF in RCC, the role of bevacizumab both as a single agent and in combination with interferon alfa has been investigated. In a randomized phase 2 study involving patients with cytokine-refractory disease, bevacizumab produced a 10% response rate and PFS of 4.8 months compared to patients treated with placebo [68]. In the AVOREN trial, the addition of bevacizumab (10 mg/kg intravenously [IV] every 2 weeks) to interferon alfa (9 million units subcutaneously [SQ] 3 times weekly) was shown to significantly increase PFS compared with interferon alfa alone (10.2 months versus 5.4 months; P = 0.0001) [47,48]. Adverse effects of this combination therapy include fatigue and asthenia. Additionally, hypertension, proteinuria, and bleeding occurred.

Tyrosine Kinase Inhibitors

TKIs have largely replaced IL-2 as first-line therapy for metastatic RCC. Axitinib, pazopanib, sorafenib, and sunitinib and can be used as first-line therapy. All of the TKIs can be used as subsequent therapy.

Sunitinib. Sunitinib is an orally administered TKI that inhibits VEGF receptor (VEGFR) types 1 and 2, PDGF receptors (PDGFR) α and β, stem cell factor receptor (c-Kit), and FLT-3 and RET kinases. Motzer and colleagues [52,53] compared sunitinib 50 mg daily orally for 4 weeks with 2 weeks off to the then standard of care, interferon alfa 9 million units SQ 3 times weekly. Sunitinib significantly increased the overall objective response rate (47% versus 12%; P < 0.001), PFS (11 versus 5 months; P < 0.001), and overall survival (26.4 versus 21.8 months; hazard ratio [HR], 0.821). The most common side effects are diarrhea, fatigue, nausea/vomiting, anorexia, hypertension, stomatitis, and hand-foot syndrome, occurring in more than 30% of patients. Often patients will require dose reductions or temporary discontinuations to tolerate therapy. Alternative dosing strategies (eg, 50 mg dose orally daily for 2 weeks alternating with 1-week free interval) have been attempted but not prospectively evaluated for efficacy [69–71].

Pazopanib. Pazopanib is an oral multi-kinase inhibitor of VEGFR types 1 and 2, PDGFR, and c-KIT. Results of a phase 3 trial comparing pazopanib (800 mg orally daily) to placebo favored the TKI, with a PFS of 9.2 months versus 4.2 months. A subset of treatment-naïve patients had a longer PFS of 11.1 versus 2.8 months and a response rate of 32% versus 4% [72]. This led to a noninferiority phase 3 trial comparing pazopanib with sunitinib as first-line therapy [50]. In this study, PFS was similar (8.4 versus 9.5 months; HR 1.05), and overall safety and quality-of-life endpoints favored pazopanib. Much less fatigue, stomatitis, hand-foot syndrome, and thrombocytopenia occurred with pazopanib, whereas hair color changes, weight loss, alopecia, and elevations of LFT enzymes occurred more frequently with pazopanib. Hypertension is common with the administration of pazopanib as well.

Sorafenib. Sorafenib is an orally administered inhibitor of Raf, serine/threonine kinase, VEGFR, PDGFR, FLT-3, c-Kit, and RET. The pivotal phase 3 Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET) compared sorafenib (400 mg orally twice daily) with placebo in patients who had progressed on prior cytokine-based therapy [73]. A final analysis, which excluded patients who were allowed to cross over therapies, found improved overall survival times (14.3 versus 1.8 months, P = 0.029) [51]. Sorafenib is associated with lower rates of diarrhea, rash, fatigue, hand-foot syndrome, alopecia, hypertension, and nausea than sunitinib, although these agents have not been compared to one another.